This proposal is the second revision of an application originally submitted in February 2003 and resubmitted in November 2003. The goal of the proposed Mentored Patient-Oriented Research Career Development Award is to build upon the previous training and experience of Michael Kotlyar, PharmD, a tenure track assistant professor in Experimental and Clinical Pharmacology and Psychiatry. Via the mentorship, training and research proposed in this application, it is expected that Dr. Kotlyar can develop into an independent, funded investigator. To further develop skills in clinical trial design, biostatistics and ethics, Dr. Kotlyar will enroll in a formal program of study leading to a Master's degree in the Clinical Research Masters Program at the University of Minnesota. Dr. Dorothy Hatsukami, PhD, the director of the Tobacco Use Research Center will serve as Dr. Kotlyar's mentor. The research will assess the effect of paroxetine on the physiological response (blood pressure, heart rate and plasma catecholamine concentrations) and psychological discomfort during laboratory-administered mental stress tasks, administered immediately after smoking a cigarette. The research will be conducted in the NIH funded General Clinical Research Center (GCRC). We hypothesize that relative to placebo;paroxetine will decrease physiological response and reduce perceived psychological discomfort during mental stress tasks. The rationale for this research is that smokers often report smoking in response to stressful situations. Smoking and stress each result physiologically in an increase in sympathetic activity. When smoking is combined with stress, these effects are additive as assessed by measures such as increases in heart rate and blood pressure. Although high reactivity to stress is known to be detrimental to cardiovascular health, there is currently no data assessing the effect of antidepressants on the physiological response to stress in smokers or during the acute smoking period. The training and mentored research project combined with the guidance provided by an interdisciplinary advisory group should well prepare the candidate for a career as an independent, successful patient-oriented researcher.